scholarly journals Exploring the Benefit of 2-Methylbutyric Acid in Patients Undergoing Hemodialysis Using a Cardiovascular Proteomics Approach

Nutrients ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 3033
Author(s):  
Ping-Hsun Wu ◽  
Yi-Wen Chiu ◽  
Hsin-Bai Zou ◽  
Cheng-Chih Hsu ◽  
Su-Chu Lee ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Multiple Testing ◽  
Acid Level ◽  
Linear Regression Analysis ◽  
Short Chain Fatty Acids ◽  
Negatively Associated ◽  
Multiple Testing Adjustment ◽  
Methylbutyric Acid ◽  
Cubic Spline Curve

Short-chain fatty acids (SCFAs) can reduce pro-inflammatory parameters and oxidative stress, providing potential cardiovascular (CV) benefits. Although some evidence links SCFAs with host metabolic health via several biological mechanisms, the role of SCFA on CV disease in patients with kidney disease remains unclear. Herein, we investigate the association between a SCFA, 2-methylbutyric acid, and target CV proteomics to explore the potential pathophysiology of SCFA-related CV benefit in patients with kidney disease. Circulating 2-methylbutyric acid was quantified by high-performance liquid chromatography and 181 CV proteins by a proximity extension assay in 163 patients undergoing hemodialysis (HD). The associations between 2-methylbutyric acid and CV proteins were evaluated using linear regression analysis with age and gender, and multiple testing adjustment. The selected CV protein in the discovery phase was further confirmed in multivariable-adjusted models and evaluated by continuous scale association. The mean value of circulating 2-methylbutyric acid was 0.22 ± 0.02 µM, which was negatively associated with bone morphogenetic protein 6 (BMP-6) according to the false discovery rate (FDR) multiple testing adjustment method. The 2-methylbutyric acid level remained negatively associated with BMP-6 (β coefficient −1.00, 95% confidence interval −1.45 to −0.55, p < 0.001) after controlling for other CV risk factors in multivariable models. The cubic spline curve demonstrated a linear relationship. In conclusion, circulating 2-methylbutyric acid level was negatively associated with BMP-6, suggesting that this pathway maybe involved in vascular health in patients undergoing HD. However, further in vitro work is still needed to validate the translation of the mechanistic pathways.

scholarly journals MO046MICROBIOTA DERIVED SHORT CHAIN FATTY ACIDS, PROPIONATE AND BUTYRATE, CONTRIBUTE TO MODULATE THE INFLAMMATORY RESPONSE IN CHRONIC KIDNEY DISEASE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Viviana Corte ◽  
Ana Cristina Andrade ◽  
Paula Diaz-Bulnes ◽  
Nuria Salazar Garzo ◽  
Jose Joaquin Bande ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Fatty Acids ◽  
Renal Function ◽  
Kidney Disease ◽  
Inflammatory Response ◽  
Gut Microbiota ◽  
Immune Cells ◽  
Short Chain Fatty Acids

Abstract Background and Aims Dysbiosis, or changes in the gut microbiota composition, had been related to the developed of several pathologies, such as chronic kidney disease. Until now, multiple studies have focused on the influence of diet on outcomes of patients with CKD. These patients with advanced disease are recommended a restricted intake of vegetable fiber due to the phosphorus and potassium levels, and low proteins to avoid the generation of uremic toxins. It is known that dietary changes lead to alterations in gut microbiota, but also in microbial metabolites production, some of which could be beneficial for the host. A recent and exciting area of research has begun to explore the role of microbiota-derived metabolites in the renal physiology. Short-chain fatty acids (SCFA, acetate, propionate and butyrate) are a type metabolite produced from dietary fiber by gut microbiota that enter in the bloodstream leading to distal effects, such as modulation of the immune cells. SCFAs are essential to maintain the permeability of the intestinal epithelial barrier, the metabolic functions and have potent anti-inflammatory effects. The aim of this study was to identify the SCFAs levels during the progression of CKD and determinate the functional role of these metabolites in the renal inflammation. Method SFCAs (acetate, propionate and butyrate) levels were determined using gas chromatography-mass spectrometry in fecal samples collected from patients with different stages of CKD (n=60) and age-matched healthy control (n=20). Moreover, common bacterial families were determined by quantitative PCR. Additionally, the in-vitro effect of the three SCFAs was evaluated in the human tubular epithelial cell line HK2 using RNA-seq, specific silencing with siRNAs and histone deacetylases (HDAC) inhibitors. To evaluate the effect in immune cells, monocyte and macrophages were treated with LPS and ATP /Nigericin to induce inflammasome activation. Results The SCFAs levels were significantly lower in patients with CKD than in healthy controls, mainly propionate and butyrate. Moreover, these levels progressively decreased with the developed of the disease, showing the patients with stage 5 (CKD5) have the lowest levels that correlates with a lesser abundance of Clostridium IV family. According to the renal function, butyrate levels were positively correlated with the glomerular filtration rate and negatively with the blood urea nitrogen and creatinine levels. Surprisingly, high propionate levels correlate with the most elevated serum calcidiol concentrations. Functionally, propionate and butyrate show a similar pattern in the modulation of inflammatory genes in HK2 cells. Most regulated pathways are associated with Inflammatory response (GO:0006954: IL6, TNF, CCL2, RELB, IRAK2, NFKB1,CCL20) and immune response (GO:0006955: CSF2, CXCL3, CD40, IL7R, LIF). Additionally, both SCFAs regulates the expression of multiple epigenetic enzymes involves in the chromatin remodeling, mainly in histone acetylation. In monocytes/macrophages, propionate and butyrate inhibits the IL1B, CASP, and ASC gene transcription damaging the IL-1β secretion. We determined that the effect of SCFAs in these in-vitro models is mediated by inhibition of HDAC although also change other histone modifications (H3K9me3, H3K27me3) and through the GPR109A receptor. Conclusion Our initial results showed that patients with advanced CKD have low levels of SCFAs, and those were correlated with the renal function. Treatment of human renal and immune cells with propionate and butyrate induces profound changes in the chromatin structure, changing the whole-genome gene expression and modulating key pathways in the renal pathology. Increasing the SCFAs levels in those patients could be a potential therapeutic strategy to slow down the disease progression.

scholarly journals Association between Serum Indoxyl Sulfate Levels and Endothelial Function in Non-Dialysis Chronic Kidney Disease

Toxins ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 589 ◽  
Author(s):  
Chih-Hsien Wang ◽  
Yu-Hsien Lai ◽  
Chiu-Huang Kuo ◽  
Yu-Li Lin ◽  
Jen-Pi Tsai ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Regression Analysis ◽  
Kidney Disease ◽  
Linear Regression ◽  
Endothelial Function ◽  
Vascular Reactivity ◽  
Linear Regression Analysis ◽  
Indoxyl Sulfate ◽  
Reactivity Index ◽  
Negatively Associated

Indoxyl sulfate (IS), a product metabolized from tryptophan, is negatively correlated with renal function and cardiovascular diseases in patients with chronic kidney disease (CKD). We investigated the association between serum IS levels and endothelial function in patients with CKD. Fasting blood samples were obtained from 110 patients with stages 3–5 CKD. The endothelial function, represented by vascular reactivity index (VRI), was measured non-invasively using digital thermal monitoring. Serum IS levels were determined using liquid chromatography–mass spectrometry. Twenty-one (19.1%), 36 (32.7%), and 53 (48.2%) patients had poor (VRI < 1.0), intermediate (1.0 ≤ VRI < 2.0), and good (VRI ≥ 2.0) vascular reactivity. By univariate linear regression analysis, a higher prevalence of smoking, advanced age, higher systolic, and diastolic blood pressure (DBP), elevated levels of serum phosphorus, blood urea nitrogen, creatinine, and IS were negatively correlated with VRI values, but estimated glomerular filtration rate negatively associated with VRI values. After being adjusted by using multivariate stepwise linear regression analysis, DBP and IS levels were significantly negatively associated with VRI values in CKD patients. We concluded that IS level associated inversely with VRI values and had a modulating role in endothelial function in patients with stages 3–5 CKD.

Dependence of Blood Clot Lysis on the Mode of Transport of Urokinase into the Clot - A Magnetic Resonance Imaging Study in Vitro

1991 ◽  
Vol 65 (05) ◽  
pp. 549-552 ◽  
Author(s):  
A Blinc ◽  
G Planinšič ◽  
D Keber ◽  
O Jarh ◽  
G Lahajnar ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Pressure Difference ◽  
Volume Flow Rate ◽  
Blood Clot ◽  
Linear Regression Analysis ◽  
Imaging Study ◽  
Clot Lysis ◽  
Resonance Imaging

SummaryMagnetic resonance imaging was employed to study the dependence of clot lysing patterns on two different modes of transport of urokinase into whole blood clots. In one group of clots (nonperfused clots, n1 = 10), access of urokinase to the fibrin network was possible by diffusion only, whereas in the other group (perfused clots, n2 = 10) bulk flow of plasma containing urokinase was instituted through occlusive clots by a pressure difference of 3 .7 kPa (37 cm H2O) across 3 cm long clots with a diameter of 4 mm. It was determined separately that this pressure difference resulted in a volume flow rate of 5.05 ± 2.4 × 10−2 ml/min through occlusive clots. Perfused clots diminished in size significantly in comparison to nonperfused ones already after 20 min (p <0.005). Linear regression analysis of two-dimensional clot sizes measured by MRI showed that the rate of lysis was more than 50-times faster in the perfused group in comparison to the nonperfused group. It was concluded that penetration of the thrombolytic agent into clots by perfusion is much more effective than by diffusion. Our results might have some implications for understanding the differences in lysis of arterial and venous thrombi.

Short-Chain Fatty Acids Prevent Diabetic Nephropathy In Vivo and In Vitro

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 92-OR ◽  
Author(s):  
WEI HUANG ◽  
YONG XU ◽  
YOUHUA XU ◽  
LUPING ZHOU ◽  
CHENLIN GAO
Keyword(s):  
Fatty Acids ◽  
Diabetic Nephropathy ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Chain Fatty Acids

scholarly journals Chemical composition and in vitro digestibility of some selected under-utilized tropical seeds as protein sources in ruminants’ diet

2020 ◽  
Vol 44 (1) ◽  
Author(s):  
Oluwatosin Bode Omotoso ◽  
Mary Oluwafunmilayo Adeduntan ◽  
Adebowale Noah Fajemisin
Keyword(s):  
Short Chain Fatty Acids ◽  
Nutritional Composition ◽  
Metabolizable Energy ◽  
In Vitro Digestibility ◽  
Protein Sources ◽  
Dry Matter Digestibility ◽  
Supplementary Feed ◽  
Monodora Myristica

Abstract Background The study highlighted the potential of three common and under-utilized tropical leguminous seeds (Tomentosa nilotica, Dioclea reflexa and Monodora myristica) to be used as supplementary feed to ruminant livestock. These seeds (their plants inclusive) are valuable sources of food and medicine for the prevention of illness and maintenance of human health. The medicinal properties of these seeds include antimicrobial, anti-inflammatory, anti-oxidant and immuno-stimulant. Trypsin inhibitors, which are common anti-nutritional factors in legumes and for monogastric animals, do not exert adverse effects in ruminants because they are degraded in the rumen. Hence, the crux of this study is to examine the effect of processing methods on the nutritional composition (proximate, fibre fractions, minerals, anti-nutrients) and in vitro digestibility of Tomentosa nilotica, Dioclea reflexa and Monodora myristica seeds and their suitability as feedstuff (protein sources) in small ruminant feed, particularly during off-season. Results From the results, raw Tomentosa nilotica and Monodora myristica have the highest crude protein (30.35% CP) and fat (22.40% EE), respectively. It is noteworthy that roasting best improve the mineral and significantly reduce the anti-nutrients observed in this study better compared to boiling and soaking methods. The highest organic matter digestibility, short-chain fatty acids, metabolizable energy and in vitro dry matter digestibility values were obtained in Dioclea reflexa compared to other test seeds. Roasting best improved the nutritive values, while Dioclea reflexa seed was rated highest for all the nutritional attributes and in vitro digestibility. Conclusions Dioclea reflexa could be incorporated in ruminants’ diet as protein source, particularly during the off-season, for improved ruminant production in Nigeria. However, in vivo study is therefore recommended to validate this report.

scholarly journals Dietary Fiber Modulates the Fermentation Patterns of Cyanidin-3-O-Glucoside in a Fiber-Type Dependent Manner

Foods ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1386
Author(s):  
Zixin Yang ◽  
Ting Huang ◽  
Ping Li ◽  
Jian Ai ◽  
Jiaxin Liu ◽  
...  
Keyword(s):  
Dietary Fiber ◽  
Fiber Type ◽  
Short Chain Fatty Acids ◽  
Dependent Manner ◽  
Dietary Fibers ◽  
Cell Wall Polysaccharides ◽  
Total Carbohydrate ◽  
In Vitro Fermentation ◽  
Gas Volume

The interactions between cell-wall polysaccharides and polyphenols in the gastrointestinal tract have attracted extensive attention. We hypothesized that dietary fiber modulates the fermentation patterns of cyanidin-3-O-glucoside (C3G) in a fiber-type-dependent manner. In the present study, the effects of four dietary fibers (fructose-oligosaccharides, pectin, β-glucan and arabinoxylan) on the modulation of C3G fermentation patterns were investigated through in vitro fermentation inoculated with human feces. The changes in gas volume, pH, total carbohydrate content, metabolites of C3G, antioxidant activity, and microbial community distribution during in vitro fermentation were analyzed. After 24 h of fermentation, the gas volume and total carbohydrate contents of the four dietary-fiber-supplemented groups respectively increased and decreased to varying degrees. The results showed that the C3G metabolites after in vitro fermentation mainly included cyanidin, protocatechuic acid, 2,4,6-trihydroxybenzoic acid, and 2,4,6-trihydroxybenzaldehyde. Supplementation of dietary fibers changed the proportions of C3G metabolites depending on the structures. Dietary fibers increased the production of short-chain fatty acids and the relative abundance of gut microbiota Bifidobacterium and Lactobacillus, thus potentially maintaining colonic health to a certain extent. In conclusion, the used dietary fibers modulate the fermentation patterns of C3G in a fiber-type-dependent manner.

scholarly journals Impact of 2′-Fucosyllactose on Gut Microbiota Composition in Adults with Chronic Gastrointestinal Conditions: Batch Culture Fermentation Model and Pilot Clinical Trial Findings

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 938
Author(s):  
Jennifer Joan Ryan ◽  
Andrea Monteagudo-Mera ◽  
Nikhat Contractor ◽  
Glenn R. Gibson
Keyword(s):  
Ulcerative Colitis ◽  
Batch Culture ◽  
Pilot Trial ◽  
Gastrointestinal Symptoms ◽  
Short Chain Fatty Acids ◽  
Open Label ◽  
Gastrointestinal Conditions ◽  
Fermentation Model ◽  
Quality Of Life Index

Intestinal dysbiosis has been described in patients with certain gastrointestinal conditions including irritable bowel syndrome (IBS) and ulcerative colitis. 2′-fucosyllactose (2′-FL), a prebiotic human milk oligosaccharide, is considered bifidogenic and butyrogenic. To assess prebiotic effects of 2′-FL, alone or in combination with probiotic strains (potential synbiotics), in vitro experiments were conducted on stool from healthy, IBS, and ulcerative colitis adult donors. In anaerobic batch culture fermenters, Bifidobacterium and Eubacterium rectale-Clostridium coccoides counts, and short-chain fatty acids (SCFAs) including butyrate increased during fermentation with 2′-FL and some of the 2′-FL/probiotic combinations. In a subsequent open-label pilot trial, the effect of a 2′-FL-containing nutritional formula was evaluated in twelve adults with IBS or ulcerative colitis. Gastrointestinal Quality of Life Index (GIQLI) total and gastrointestinal symptoms domain scores, stool counts of Bifidobacterium and Faecalibacterium prausnitzii, and stool SCFAs including butyrate, increased after six weeks of intervention. Consistent with documented effects of 2′-FL, the batch culture fermentation experiments demonstrated bifidogenic and butyrogenic effects of 2′-FL during fermentation with human stool samples. Consumption of the 2′-FL-containing nutritional formula by adults with IBS or ulcerative colitis was associated with improvements in intra- and extra-intestinal symptoms, and bifidogenic and butyrogenic effects.

scholarly journals Xylitol enhances synthesis of propionate in the colon via cross-feeding of gut microbiota

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Shasha Xiang ◽  
Kun Ye ◽  
Mian Li ◽  
Jian Ying ◽  
Huanhuan Wang ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Lactobacillus Reuteri ◽  
Carbon Sources ◽  
Short Chain Fatty Acids ◽  
Microbial Composition ◽  
Key Enzymes ◽  
Rrna Sequencing ◽  
Phosphate Acetyltransferase

Abstract Background Xylitol, a white or transparent polyol or sugar alcohol, is digestible by colonic microorganisms and promotes the proliferation of beneficial bacteria and the production of short-chain fatty acids (SCFAs), but the mechanism underlying these effects remains unknown. We studied mice fed with 0%, 2% (2.17 g/kg/day), or 5% (5.42 g/kg/day) (weight/weight) xylitol in their chow for 3 months. In addition to the in vivo digestion experiments in mice, 3% (weight/volume) (0.27 g/kg/day for a human being) xylitol was added to a colon simulation system (CDMN) for 7 days. We performed 16S rRNA sequencing, beneficial metabolism biomarker quantification, metabolome, and metatranscriptome analyses to investigate the prebiotic mechanism of xylitol. The representative bacteria related to xylitol digestion were selected for single cultivation and co-culture of two and three bacteria to explore the microbial digestion and utilization of xylitol in media with glucose, xylitol, mixed carbon sources, or no-carbon sources. Besides, the mechanisms underlying the shift in the microbial composition and SCFAs were explored in molecular contexts. Results In both in vivo and in vitro experiments, we found that xylitol did not significantly influence the structure of the gut microbiome. However, it increased all SCFAs, especially propionate in the lumen and butyrate in the mucosa, with a shift in its corresponding bacteria in vitro. Cross-feeding, a relationship in which one organism consumes metabolites excreted by the other, was observed among Lactobacillus reuteri, Bacteroides fragilis, and Escherichia coli in the utilization of xylitol. At the molecular level, we revealed that xylitol dehydrogenase (EC 1.1.1.14), xylulokinase (EC 2.7.1.17), and xylulose phosphate isomerase (EC 5.1.3.1) were key enzymes in xylitol metabolism and were present in Bacteroides and Lachnospiraceae. Therefore, they are considered keystone bacteria in xylitol digestion. Also, xylitol affected the metabolic pathway of propionate, significantly promoting the transcription of phosphate acetyltransferase (EC 2.3.1.8) in Bifidobacterium and increasing the production of propionate. Conclusions Our results revealed that those key enzymes for xylitol digestion from different bacteria can together support the growth of micro-ecology, but they also enhanced the concentration of propionate, which lowered pH to restrict relative amounts of Escherichia and Staphylococcus. Based on the cross-feeding and competition among those bacteria, xylitol can dynamically balance proportions of the gut microbiome to promote enzymes related to xylitol metabolism and SCFAs.

scholarly journals Inhibition of Kirsten-Ras reduces fibrosis and protects against renal dysfunction in a mouse model of chronic folic acid nephropathy

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Lucy J. Newbury ◽  
Jui-Hui Wang ◽  
Gene Hung ◽  
Bruce M. Hendry ◽  
Claire C. Sharpe
Keyword(s):  
Folic Acid ◽  
Kidney Disease ◽  
Mouse Model ◽  
Renal Dysfunction ◽  
Antisense Oligonucleotides ◽  
Underlying Mechanism ◽  
Therapeutic Benefit ◽  
End Stage

Abstract Chronic Kidney Disease is a growing problem across the world and can lead to end-stage kidney disease and cardiovascular disease. Fibrosis is the underlying mechanism that leads to organ dysfunction, but as yet we have no therapeutics that can influence this process. Ras monomeric GTPases are master regulators that direct many of the cytokines known to drive fibrosis to downstream effector cascades. We have previously shown that K-Ras is a key isoform that drives fibrosis in the kidney. Here we demonstrate that K-Ras expression and activation are increased in rodent models of CKD. By knocking down expression of K-Ras using antisense oligonucleotides in a mouse model of chronic folic acid nephropathy we can reduce fibrosis by 50% and prevent the loss of renal function over 3 months. In addition, we have demonstrated in vitro and in vivo that reduction of K-Ras expression is associated with a reduction in Jag1 expression; we hypothesise this is the mechanism by which targeting K-Ras has therapeutic benefit. In conclusion, targeting K-Ras expression with antisense oligonucleotides in a mouse model of CKD prevents fibrosis and protects against renal dysfunction.

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